Ethyne-bridged (porphinato)zinc(II)-(porphinato)iron(III) complexes: phenomenological dependence of excited-state dynamics upon (porphinato)iron electronic structure.
We report the synthesis, spectroscopy, potentiometric properties, and excited-state dynamical studies of 5-[(10,20-di-((4-ethyl ester)methylene-oxy)phenyl)porphinato]zinc(II)-[5'-[(10',20'- di-((4-ethyl ester)methylene-oxy)phenyl)porphinato]iron(III)-chloride]ethyne (PZn-PFe-Cl), along with a series of related supermolecules ([PZn-PFe-(L)1,2]+ species) that possess a range of metal axial ligation environments (L = pyridine, 4-cyanopyridine, 2,4,6-trimethylpyridine (collidine), and 2,6-dimethylpyridine (2,6-lutidine)). Relevant monomeric [(porphinato)iron-(ligand)1,2]+ ([PFe(L)1,2]+) benchmarks have also been synthesized and fully characterized. Ultrafast pump-probe transient absorption spectroscopic experiments that interrogate the initially prepared electronically excited states of [PFe(L)1,2]+ species bearing nonhindered axial ligands demonstrated subpicosecond-to-picosecond relaxation dynamics to the ground electronic state. Comparative pump-probe transient absorption experiments that interrogate the initially prepared excited states of PZn-PFe-Cl, [PZn-PFe-(py)2]+, [PZn-PFe-(4-CN-py)2]+, [PZn-PFe-(collidine)]+, and [PZn-PFe-(2,6-lutidine)]+ demonstrate that the spectra of all these species are dominated by a broad, intense NIR S1 --> Sn transient absorption manifold. While PZn-PFe-Cl, [PZn-PFe-(py)2]+, and [PZn-PFe-(4-CN-py)2]+ evince subpicosecond and picosecond time-scale relaxation of their respective initially prepared electronically excited states to the ground state, the excited-state dynamics observed for [PZn-PFe-(2,6-lutidine)]+ and [PZn-PFe-(collidine)]+ show fast relaxation to a [PZn+-PFe(II)] charge-separated state having a lifetime of nearly 1 ns. Potentiometric data indicate that while DeltaGCS for [PZn-PFe-(L)1,2]+ species is strongly influenced by the PFe+ ligation state [ligand (DeltaGCS): 4-cyanopyridine (-0.79 eV) < pyridine (-1.04 eV) < collidine (-1.35 eV) < chloride (-1.40 eV); solvent = CH2Cl2], the pump-probe transient absorption dynamical data demonstrate that the nature of the dominant excited-state decay pathway is not correlated with the thermodynamic driving force for photoinduced charge separation, but depends on the ferric ion ligation mode. These data indicate that sterically bulky axial ligands that drive a pentacoordinate PFe center and a weak metal axial ligand interaction serve to sufficiently suppress the normally large magnitude nonradiative decay rate constants characteristic of (porphinato)iron(III) complexes, and thus make electron transfer a competitive excited-state deactivation pathway.


[Cerebrovascular accident as the form of presentation of a pancreatic cystadenocarcinoma: an unusual form of presentation in a rare tumor].
Pancreatic cystadenocarcinoma is an uncommon neoplasm of the pancreas. Mucinous cystadenocarcinoma is the most frequent pancreatic cystadenocarcinoma. Symptoms are often non-specific but abdominal pain and jaundice are common in tumors localized in the head of the pancreas. Thromboembolic manifestations of pancreatic neoplasm have been described but are infrequent. The commonest manifestations are migratory thrombophlebitis, mesenteric venous thrombosis and pulmonary embolism. Cerebral stroke as the first manifestation of pancreatic carcinoma is exceptional. The mechanism by which pancreatic carcinoma induces stroke is unclear, although Trousseau's syndrome, complications of mucinous cancer or blood disorders could play a role. We report the case of a young woman with transient stroke and paraneoplastic thrombocytosis in whom pancreatic cystadenocarcinoma was diagnosed.


Serial computed tomographic evaluation in desquamative interstitial pneumonia.
Desquamative interstitial pneumonia (DIP) may represent the early stage and usual interstitial pneumonia (UIP) the late stage of the same disease. The purpose of this study was to evaluate the computed tomographic (CT) features of DIP, to evaluate the changes in pattern and extent of disease over time, and to determine whether the appearances of DIP on the CT scan change to those of UIP during follow up. Sequential CT evaluation was conducted on eight patients with DIP over a mean (SD) follow up period of 3.2 (1.3) years (range 1.6-6.5). The relative extents of ground glass and honeycombing were determined from serial CT scans. Changes in the extent and appearance of the disease were examined in paired anatomically comparable CT sections. Common features on the CT scans of patients with DIP were a homogeneous increase in lung attenuation (n = 5), linear areas of attenuation (n = 5), relatively well preserved lung architecture (n = 5), and the presence of small cysts (n = 6). Uncommon features were architectural distortion (n = 3), and traction bronchiectasis (n = 1). In six patients with DIP with cystic spaces these did not change with time in three cases, in two they regreased, and in one patient they increased. Open lung biopsy samples from patients with DIP with many cystic lesions showed dilated alveolar ducts and bronchioles and/or pulmonary cysts, as well as numerous macrophage-filled air spaces and mild fibrosis, but no typical honeycomb cysts were seen. Some of the microcysts in DIP are different from the honeycomb cysts seen in UIP, and some of the cysts seen in patients with DIP resolve with time. DIP does not progress to UIP in the short term.


Exosomes: The Link between GPCR Activation and Metastatic Potential?
The activation of G-Protein Coupled Receptors (GPCRs) by their respective ligands initiates a cascade of multiple signaling processes within the cell, regulating growth, metabolism and other essential cellular functions. Dysregulation and aberrant expression of these GPCRs and their subsequent signaling cascades are associated with many different types of pathologies, including cancer. The main life threatening complication in patients diagnosed with cancer is the dissemination of cells from the primary tumor to distant vital organs within the body, metastasis. Communication between the primary tumor, immune system, and the site of future metastasis are some of the key events in the early stages of metastasis. It has been postulated that the communication is mediated by nanovesicles that, under non-pathological conditions, are released by normal cells to relay signals to other cells in the body. These nanovesicles are called exosomes, and are utilized by the tumor cell to influence changes within the recipient cell, such as bone marrow progenitor cells, and cells within the site of future metastatic growth, in order to prepare the site for colonization. Tumor cells have been shown to release an increased number of exosomes when compared to their normal cell counterpart. Exosome production and release are regulated by proteins involved in localization, degradation and size of the multivesicular body, whose function may be altered within cancer cells, resulting in the release of an increased number of these vesicles. This review investigates the possibility of GPCR signaling cascades acting as the upstream activator of proteins involved in exosome production and release, linking a commonly targeted trans-membrane protein class with cellular communication utilized by tumor cells in early stages of metastasis.


Regulation of Sucrose non-Fermenting Related Kinase 1 genes in Arabidopsis thaliana.
The Sucrose non-Fermenting Related Kinase 1 (SnRK1) proteins have been linked to regulation of energy and stress signaling in eukaryotes. In plants, there is a small SnRK1 gene family. While the SnRK1.1 gene has been well studied, the role other SnRK1 isoforms play in energy or stress signaling is less well understood. We used promoter:GUS analysis and found SnRK1.1 is broadly expressed, while SnRK1.2 is spatially restricted. SnRK1.2 is expressed most abundantly in hydathodes, at the base of leaf primordia, and in vascular tissues within both shoots and roots. We examined the impact that sugars have on SnRK1 gene expression and found that trehalose induces SnRK1.2 expression. Given that the SnRK1.1 and SnRK1.2 proteins are very similar at the amino acid level, we sought to address whether SnRK1.2 is capable of re-programming growth and development as has been seen previously with SnRK1.1 overexpression. While gain-of-function transgenic plants overexpressing two different isoforms of SnRK1.1 flower late as seen previously in other SnRK1.1 overexpressors, SnRK1.2 overexpressors flower early. In addition, SnRK1.2 overexpressors have increased leaf size and rosette diameter during early development, which is the opposite of SnRK1.1 overexpressors. We also investigated whether SnRK1.2 was localized to similar subcellular compartments as SnRK1.1, and found that both accumulate in the nucleus and cytoplasm in transient expression assays. In addition, we found SnRK1.1 accumulates in small puncta that appear after a mechanical wounding stress. Together, these data suggest key differences in regulation of the SnRK1.1 and SnRK1.2 genes in plants, and highlights differences overexpression of each gene has on the development of Arabidopsis.


Efficacy of Intravenous Reslizumab in Oral Corticosteroid-Dependent Asthma.
Reslizumab displays efficacy in patients with inadequately controlled eosinophilic asthma; previous reports in oral corticosteroid-dependent asthma are limited. To assess efficacy of reslizumab in oral corticosteroid-dependent patients and benefits on oral corticosteroid burden. We report post hoc analyses of pooled data from duplicate, placebo-controlled phase 3 trials. Patients aged 12 to 75 years with inadequately controlled, moderate-to-severe asthma were randomized 1:1 to receive intravenous reslizumab 3.0 mg/kg or placebo every 4 weeks for 52 weeks, stratified by oral corticosteroid use at enrollment and by region. Assessments included efficacy and predictors of clinical asthma exacerbation response in oral corticosteroid-dependent patients, and systemic corticosteroids burden in the overall population. Patients were randomized to reslizumab (n = 477) or placebo (n = 476); 73 (15%) patients in each group were taking oral corticosteroids at baseline. Reslizumab was favored over placebo for all efficacy end points in oral corticosteroid-dependent patients, with numerically greater improvements in oral corticosteroid-dependent patients than the overall population. Having 2 or more versus 1 clinical asthma exacerbation in the previous 12 months was the strongest positive predictor of reduced exacerbation risk with reslizumab (risk reduction, 77.5% vs 15.2%; P ≤ .02). Significantly fewer new systemic corticosteroid prescriptions were issued per patient receiving reslizumab versus placebo (mean ± SD, 0.5 ± 1.07 vs 1.0 ± 1.52; P < .0001). Total and per-patient systemic corticosteroid burdens were lower: 121,135 versus 290,977 mg and 254 versus 611 mg/patient, respectively (both P < .0001). Oral corticosteroid-dependent patients benefited from reslizumab across asthma efficacy outcome measures. Reslizumab-treated patients required fewer new systemic corticosteroid prescriptions and had a lower systemic corticosteroid burden compared with placebo.


Effects of PEGylation and acetylation of PAMAM dendrimers on DNA binding, cytotoxicity and in vitro transfection efficiency.
Poly(amidoamine) (PAMAM) dendrimers are promising multipotent gene delivery vectors, providing favorable DNA condensation properties also in combination with the possibility of conjugation of different targeting ligands to their surface. They have been used for transfection both in vitro and in vivo, but their application is currently somewhat limited due to inherent cytotoxicity. In this work we investigate how two types of surface modification, acetylation and PEGylation, affect the DNA binding characteristics, the cytotoxicity and the in vitro transfection efficiency of generation 4 and 5 PAMAM dendrimers. Particularly, we address how the morphology of DNA-dendrimer complexes, formed under low salt conditions, changes upon dilution in cell growth medium, an event that inevitably occurs before the complexes reach the cell surface in any transfection experiment. We find that acetylation and PEGylation essentially eliminates the inherent dendrimer cytotoxicity. However, the transfection efficiency of the modified dendrimers is lower than that of the corresponding unmodified dendrimers, which can be rationally understood by our observations that DNA is less condensed when complexed with these modified dendrimers. Although small DNA-dendrimer particles are formed, the availability for ethidium intercalation and nuclease degradation is significantly higher in the modified DNA-dendrimer complexes than in unmodified ones. Dilution in cell growth medium has a drastic effect on these electrostatically assembled complexes, resulting in increase in size and DNA availability. Our results strongly add to the notion that it is of importance to perform a biophysical characterization under conditions as close to the transfection situation as possible, to enable conclusions regarding structure-activity relations of gene delivery vectors.


Impaired Recognition of Mycobacterium tuberculosis by Alveolar Macrophages From Diabetic Mice.
Diabetes mellitus is associated with increased tuberculosis risk and severity. We previously reported that tuberculosis susceptibility in diabetic mice results from a delay in innate immune response to inhaled Mycobacterium tuberculosis, leading to delayed adaptive immune priming and, consequently, a higher plateau lung bacterial burden and greater immune pathology. We tested the capacity of alveolar macrophages from diabetic mice to phagocytose M. tuberculosis ex vivo and promote T-cell activation in vivo. Alveolar macrophages from diabetic mice had reduced expression of CD14 and macrophage receptor with collagenous structure (MARCO), which recognize the bacterial cell wall component trehalose 6,6'-dimycolate (TDM). Diabetic alveolar macrophages exhibited reduced phagocytosis of M. tuberculosis or TDM-coated latex beads. This alveolar macrophage phenotype was absent in peritoneal and bone marrow-derived macrophages. Transfer of infected alveolar macrophages from diabetic mice into nondiabetic recipients confirmed an intrinsic alveolar macrophage defect that hindered T-cell priming. The diabetic alveolar macrophage phenotype depended in part on expression of the receptor for advanced glycation end products. Reduced MARCO and CD14 expression contributes to defective sentinel function of alveolar macrophages, promoting tuberculosis susceptibility in diabetic hosts at a critical early step in the immune response to aerosol infection.


Parity-Time Symmetry Breaking in Coupled Nanobeam Cavities.
The concept of parity-time symmetry (PT symmetry) originates from the canonical quantum mechanics and has become a hot topic recently. As a versatile platform to investigate the intriguing concept, both theoretical and experimental works in optics have been implemented. In this paper, the PT symmetry breaking phenomenon is investigated in a coupled nanobeam cavity system. An exceptional point is observed during the tuning of the gain/loss level and the coupling strength of the closely placed nanobeam pair. Unidirectional light propagation is investigated, as well as enhanced sensitivity of single particle detection in the vicinity of the exceptional point. The proposed system is easy to be integrated with photonic integrated circuits and can be strongly coupled to optical waveguides.


Comparison of Xpert Flu rapid nucleic acid testing with rapid antigen testing for the diagnosis of influenza A and B.
Influenza infections are associated with thousands of hospital admissions and deaths each year. Rapid detection of influenza is important for prompt initiation of antiviral therapy and appropriate patient triage. In this study the Cepheid Xpert Flu assay was compared with two rapid antigen tests, BinaxNOW Influenza A & B and BD Directigen EZ Flu A+B, as well as direct fluorescent antibody testing for the rapid detection of influenza A and B. Using real-time, hydrolysis probe-based, reverse transcriptase PCR as the reference method, influenza A sensitivity was 97.3% for Xpert Flu, 95.9% for direct fluorescent antibody testing, 62.2% for BinaxNOW, and 71.6% for BD Directigen. Influenza B sensitivity was 100% for Xpert Flu and direct fluorescent antibody testing, 54.5% for BinaxNOW, and 48.5% for BD Directigen. Specificity for influenza A was 100% for Xpert Flu, BinaxNOW, and BD Directigen, and 99.2% for direct fluorescent antibody testing. All methods demonstrated 100% specificity for influenza B. These findings support the use of the Xpert Flu assay in settings requiring urgent diagnosis of influenza A and B.


Baja california: late cretaceous dinosaurs.
Late Cretaceous dinosaurs have been discovered along the Pacific margin of Baja California. The presence of Hypacrosaurus sp. is suggestive of correlation with the Upper Edmonton Formation, Alberta. Dissimilarities between the Baja California fauna and those from contemporary units along the eastern trend of the Rocky Mountains suggest that Baja California was ecologically separated from mainland Mexico during late Campanian and early Maastrictian time.


Lactoferrin and iron: structural and dynamic aspects of binding and release.
Lactoferrin (Lf) has long been recognized as a member of the transferrin family of proteins and an important regulator of the levels of free iron in the body fluids of mammals. Its ability to bind ferric iron with high affinity (KD approximately 10(-20) M) and to retain it to low pH gives the protein bacteriostatic and antioxidant properties. This ability can be well understood in terms of its three dimensional (3D) structure. The molecule is folded into two homologous lobes (N- and C-lobes) with each lobe binding a single Fe3+ ion in a deep cleft between two domains. The iron sites are highly conserved, and highly favorable for iron binding. Iron binding and release are associated with large conformational changes in which the protein adopts either open or closed states. Comparison of available apolactoferrin structures suggests that iron binding is dependent on the dynamics of the open state. What triggers release of the tightly bound iron, however, and why lactoferrin retains iron to much lower pH than its serum homologue, transferrin, has been the subject of much speculation. Comparisons of structural and functional data on lactoferrins and transferrins now suggest that the key factor comes from cooperative interactions between the two lobes of the molecule, mediated by two alpha-helices.


p27(Kip1) V109G polymorphism and cancer risk: a systematic review and meta-analysis.
Relationship between the p27Kip1 (here after referred to as p27) V109G polymorphism and cancer risk has been extensively studied; however, results from different studies were not fully consistent. Therefore, we carried out a meta-analysis to comprehensively assess the correlation between the p27V109G polymorphism and the cancer risk. Articles on the relationship of the p27V109G polymorphism with cancer risk were searched from Medline, Pub Med, and Web of science databases. A total of eight eligible studies with 3591 cases and 3799 controls were included in this meta-analysis. Overall, it seemed that the G allele was not associated with the elevated cancer risk (pooled odds ratio [OR]=0.98, 95% confidence interval [CI]: 0.88-1.09, p=0.68, fixed effects). Analyses in different populations revealed that no statistically significant associations between the G allele and cancer risk were demonstrated in Caucasians or Asians. When analyzed in different types of cancer that, from two studies, the G allele was found to be associated with a decreased risk of prostate cancer in a dominant genetic model (pooled OR=0.60, 95% CI=0.36-0.98, p=0.04, fixed effects), but did not alter the breast cancer risk from four studies. In conclusion, this meta-analysis indicated that the p27V109G polymorphism did not correlate with the overall cancer risk in the general population.


Pancreatoblastoma: Cytologic and histologic analysis of 12 adult cases reveals helpful criteria in their diagnosis and distinction from common mimics.
Pancreatoblastoma (PBL) is a rare malignant pancreatic tumor seen predominantly in childhood, and its cytologic diagnosis remains challenging. Twelve fine-needle-aspirations from 11 adults were analyzed. In total, 6 men and 5 women (median age, 45 years; age range, 32-60 years) had tumors measuring a median 5.6 cm (range, 2.5-12 cm) located in the pancreatic head (n = 7) or tail (n = 4), including 3 with familial adenomatous polyposis (FAP)/FAP-related syndromes and 4 with metastasis at diagnosis. The median follow-up was 39.8 months (range, 0.8-348 months), and 5 patients died of disease. The original cytology diagnoses were: PBL (n = 2), neuroendocrine neoplasm (n = 2), poorly differentiated neuroendocrine carcinoma (n = 2), well differentiated neuroendocrine tumor (n = 1), poorly differentiated carcinoma (n = 2), "positive for malignancy" (n = 1), acinar cell carcinoma (n = 1), and epithelioid neoplasm with endocrine and acinar differentiation versus PBL (n = 1). Universal cytopathologic findings included hypercellularity; 3-dimensional clusters; and single, monotonous, blast-like cells that were from 1.5 to 2.0 times the size of red blood cells with high nuclear-to-cytoplasmic ratio, fine chromatin, small, distinct nucleoli, and a resemblance to well differentiated neuroendocrine tumor and poorly differentiated neuroendocrine carcinoma. Branching pseudopapillae (n = 7) and grooved nuclei (n = 3) raised the differential diagnosis of solid-pseudopapillary neoplasm, but with more atypia. Uncommon features included pleomorphism (n = 4) and numerous mitoses (n = 1). Squamoid morules were seen on smears (n = 5) or cell blocks (n = 6) in 70% of patients and were characterized by epithelioid cells with elongated, streaming nuclei, fine chromatin, absent nucleoli, and positive nuclear β-catenin (n = 6 of 8). The median Ki-67 index was 21% (range, 2%-70%), and neuroendocrine marker expression was common (100%), but acinar markers were variable (63%). A combination of cytologic findings in PBL, including a predominant population of primitive blast-like cells, subtle squamoid morules, frequent neuroendocrine and variable acinar phenotype, should facilitate accurate cytologic diagnosis and distinction from common mimics.


Endoscopic endonasal approach for craniopharyngioma: the importance of the relationship between pituitary stalk and tumor.
OBJECTIVE The endoscopic endonasal approach (EEA) is commonly used for the treatment of craniopharyngioma; therefore, it is essential to analyze outcomes in order to understand the benefits and drawbacks. The goal of this paper was to evaluate the clinical features and outcomes associated with this treatment approach. METHODS From July 2010 to March 2016, 82 adult craniopharyngioma patients underwent an EEA at the authors' institution. Of these cases, intraoperative records and immediate postoperative MR images were available for 68 patients. The patients underwent systemized endocrinological evaluation. Eighteen of 68 patients who underwent EEA for recurrence or regrowth of residual lesions after previous surgical management were excluded in the analysis of the anatomical tumor classification. The authors retrospectively analyzed preoperative clinical features and previous anatomical classifications, focusing on the relationship of the pituitary stalk and tumor, to determine predictive factors for the clinical outcome, such as the extent of resection, visual function, endocrinological function, recurrence rate, and complications. RESULTS The mean tumor size was 2.5 cm (3.1 cm for primary tumors and 1.9 cm for recurrent lesions). Gross-total resection (GTR) was achieved in 62 (91.1%) patients (48 [96.0%] patients with primary tumors and 14 [77.8%] patients with recurrent tumors). The rate of GTR was higher in the primary group than in the group with recurrence (p = 0.038). The overall pre- and postoperative visual impairment scale (VIS) scores were 40.8 and 22.1, respectively (50.9 and 14.3 in the primary group and 30.7 and 29.9 in patients with recurrence, respectively). The improvement rate in VIS score was higher in the primary group than in the recurrent group (p = 0.001). Endocrinological function was improved in 4 patients (5.9%) and deteriorated in 32 of 68 patients (47.1%). Tumor invasion into the center of the pituitary stalk affected the postoperative outcomes most significantly. Cognitive dysfunction was observed in 22 patients before surgery and improved in 20 patients (90.9%) after surgery. Hydrocephalus was found in 7 patients and resolved after surgery in all cases. CSF leakage occurred in 2 (2.9%) of 68 patients and was repaired by revision surgery in both patients. Ten patients without CSF leakage also received antibiotics for the treatment of meningitis. The infection rate was higher in the recurrent group. Postoperative endocrinological evaluation showed no deficits in 12 patients and panhypopituitarism in 55 patients. The remaining patient had growth hormone deficiency. Forty-three patients had new-onset diabetes insipidus, and 1 patient had persistent diabetes insipidus after surgery. There were 2 (2.9%) cases of recurrence during the mean 30.7-month follow-up period; one patient underwent radiosurgery and the other underwent reoperation. CONCLUSIONS The EEA resulted in excellent surgical outcomes and acceptable morbidity rates, regardless of the anatomical location of the tumor. Invasion of the craniopharyngioma into the center of the pituitary stalk has strong predictive power for postoperative endocrinological outcome.


Mindful Self-Compassion Training Reduces Stress and Burnout Symptoms Among Practicing Psychologists: A Randomized Controlled Trial of a Brief Web-Based Intervention.
Objective: The aims of this study were (a) to examine the effects of a 6 weeks web-based mindful self-compassion program on stress and burnout symptoms in a group of practicing psychologists, and (b) to examine relationships between changes in self-compassion and self-coldness and changes in stress and burnout symptoms. Method: In a randomized controlled trial, 101 practicing psychologists were assigned to a training group (n = 51) or a wait-list control group (n = 49). The training encompassed 15 min exercises per day, 6 days a week, for 6 weeks. The participants completed the Self-Compassion Scale (SCS), the Five Facets of Mindfulness Questionnaire (FFMQ), the Perceived Stress Scale (PSS), and the Shirom Melamed Burnout Questionnaire (SMBQ) pre and post intervention. Results: Eighty-one participants (n = 40 in the training group, n = 41 in the control group) took part in the pre and post intervention assessments. Selective gains for the intervention group were observed for SCS total scores (d = 0.86; d = 0.94 for the SCS), FFMQ scores (d = 0.60), while levels of self-coldness was reduced (d = 0.73). Critically, levels of perceived stress (d = 0.59) and burnout symptoms (d = 0.44 for SMBQ total) were additionally lowered post intervention. Finally, the results confirmed the hypothesis that the measures of distress would be more strongly related to self-coldness than self-compassion, a pattern seen in cross-sectional analyses and, for burnout, also in the longitudinal analyses. Conclusions: This training program appeared effective to increase self-compassion/reduce self-coldness, and to alleviate stress and symptoms of burnout and provide support of the distinction between self-compassion and self-coldness. Additional studies, preferably three-armed RCTs with long-term follow-up, are warranted to further evaluate the effectiveness of the program.


Efficacy of immune checkpoint inhibitors in alveolar soft-part sarcoma: results from a retrospective worldwide registry.
Conventional cytotoxic drugs are not effective in alveolar soft-part sarcoma (ASPS). Immune checkpoint (programmed cell death protein 1/programmed death-ligand 1) inhibitors (ICIs) are promising drugs in ASPS. A worldwide registry explored the efficacy of ICI in ASPS. Data from adult patients diagnosed with ASPS and treated with ICI for advanced disease in expert sarcoma centers from Europe, Australia and North America were retrospectively collected, including demographics and data related to treatments and outcome. Seventy-six ASPS patients, with a median age at diagnosis of 25 years (range 3-61 years), were registered. All patients received ICI for metastatic disease. Immunotherapy regimens consisted of monotherapy in 38 patients (50%) and combination in 38 (50%) (23 with a tyrosine kinase inhibitor). Among the 68 assessable patients, there were 3 complete responses and 34 partial responses, translating into an overall response rate of 54.4%. After a median follow-up of 36 months [95% confidence interval (CI) 32-40 months] since the start of immunotherapy, 45 (59%) patients have progressed on ICI, with a median progression-free survival (PFS) of 16.3 months (95% CI 8-25 months). Receiving ICI in first line (P = 0.042) and achieving an objective response (P = 0.043) correlated with a better PFS. Median estimated overall survival (OS) from ICI initiation has not been reached. The 12-month and 24-month OS rates were 94% and 81%, respectively. This registry constitutes the largest available series of ASPS treated with ICI. Our results suggest that the ICI treatment provides long-lasting disease control and prolonged OS in patients with advanced ASPS, an ultra-rare entity with limited active therapeutic options.


Enhanced Phytoremediation of Crude Oil-Polluted Soil by Four Plant Species: Effect of Inorganic and Organic Bioaugumentation.
A field experiment investigating the removal and/or uptake of Polycyclic Aromatic Hydrocarbons (PAHs) and specific metals (As, Cd, Cr) from a crude oil polluted agricultural soil was performed during the 2013 wet season using four plant species: Fimbristylis littoralis, Hevea brasilensis (Rubber plants), Cymbopogom citratus (Lemon grass), and Vigna subterranea (Bambara nuts). Soil functional diversity and soil-enzyme interactions were also investigated. The diagnostic ratios and the correlation analysis identified mixed petrogenic and pyrogenic sources as the main contributors of PAHs at the study site. A total of 16 PAHs were identified, 6 of which were carcinogenic. Up to 42.4 mg kg(-1) total PAHs was recorded prior to the experiments. At 90 d, up to 92% total PAH reduction and 96% As removal were achieved using F. littoralis, the best performing species. The organic soil amendment (poultry dung) rendered most of the studied contaminants unavailable for uptake. However, the organic amendment accounted for over 70% of the increased dehydrogenase, phosphatase, and proteolytic enzymes activities in the study. Overall, the combined use of soil amendments and phytoremediation significantly improved the microbial community activity, thus promoting the restoration of the ecosystem.


Selumetinib in Combination With Dacarbazine in Patients With Metastatic Uveal Melanoma: A Phase III, Multicenter, Randomized Trial (SUMIT).
Purpose Uveal melanoma is the most common primary intraocular malignancy in adults with no effective systemic treatment option in the metastatic setting. Selumetinib (AZD6244, ARRY-142886) is an oral, potent, and selective MEK1/2 inhibitor with a short half-life, which demonstrated single-agent activity in patients with metastatic uveal melanoma in a randomized phase II trial. Methods The Selumetinib (AZD6244: ARRY-142886) (Hyd-Sulfate) in Metastatic Uveal Melanoma (SUMIT) study was a phase III, double-blind trial ( ClinicalTrial.gov identifier: NCT01974752) in which patients with metastatic uveal melanoma and no prior systemic therapy were randomly assigned (3:1) to selumetinib (75 mg twice daily) plus dacarbazine (1,000 mg/m2 intravenously on day 1 of every 21-day cycle) or placebo plus dacarbazine. The primary end point was progression-free survival (PFS) by blinded independent central radiologic review. Secondary end points included overall survival and objective response rate. Results A total of 129 patients were randomly assigned to receive selumetinib plus dacarbazine (n = 97) or placebo plus dacarbazine (n = 32). In the selumetinib plus dacarbazine group, 82 patients (85%) experienced a PFS event, compared with 24 (75%) in the placebo plus dacarbazine group (median, 2.8 v 1.8 months); the hazard ratio for PFS was 0.78 (95% CI, 0.48 to 1.27; two-sided P = .32). The objective response rate was 3% with selumetinib plus dacarbazine and 0% with placebo plus dacarbazine (two-sided P = .36). At 37% maturity (n = 48 deaths), analysis of overall survival gave a hazard ratio of 0.75 (95% CI, 0.39 to 1.46; two-sided P = .40). The most frequently reported adverse events (selumetinib plus dacarbazine v placebo plus dacarbazine) were nausea (62% v 19%), rash (57% v 6%), fatigue (44% v 47%), diarrhea (44% v 22%), and peripheral edema (43% v 6%). Conclusion In patients with metastatic uveal melanoma, the combination of selumetinib plus dacarbazine had a tolerable safety profile but did not significantly improve PFS compared with placebo plus dacarbazine.


Optimized approach in cardiocerebral resuscitation.
Cardiocerebral Resuscitation (CCR) is a new approach to the resuscitation of patients with out-of-hospital cardiac arrest (OHCA). The first major component of CCR is continuous chest compressions (also referred to as chest compression-only CPR or "hands-only CPR") advocated as part of CCR for all bystanders who witness a sudden collapse of presumed cardiac origin. The second component of CCR is a new ACLS treatment algorithm for Emergency Medical Services. This algorithm emphasizes uninterrupted chest compressions regardless of other ongoing assignments as part of the rescue effort. A third component has recently been added to CCR, namely aggressive post-resuscitation care. Cardiocerebral resuscitation has increased bystander participation and has improved survival rates in a number of communities. Now is the time for other communities to re-examine their own outcomes with cardiac arrest and consider joining those cities and communities that have doubled and even tripled their survival from OHCA.


Natural Phenolic Compounds as Therapeutic and Preventive Agents for Cerebral Amyloidosis.
Epidemiological studies have suggested that diets rich in phenolic compounds may have preventive effects on the development of dementia or Alzheimer's disease (AD). We investigated the effects of natural phenolic compounds, such as myricetin (Myr), rosmarinic acid (RA), ferulic acid (FA), curcumin (Cur) and nordihydroguaiaretic acid (NDGA) on the aggregation of amyloid β-protein (Aβ), using in vitro and in vivo models of cerebral Aβ amyloidosis. The in vitro studies revealed that these phenolic compounds efficiently inhibit oligomerization as well as fibril formation of Aβ through differential binding, whilst reducing Aβ oligomer-induced synaptic and neuronal toxicity. Furthermore, a transgenic mouse model fed orally with such phenolic compounds showed significant reduction of soluble Aβ oligomers as well as of insoluble Aβ deposition in the brain. These data, together with an updated review of the literature, indicate that natural phenolic compounds have anti-amyloidogenic effects on Aβ in addition to well-known anti-oxidative and anti-inflammatory effects, hence suggesting their potential as therapeutic and/or preventive agents for cerebral Aβ amyloidosis, including AD and cerebral amyloid angiopathy (CAA). Well-designed clinical trials or preventive interventions with natural phenolic compounds are necessary to establish their efficacy as disease-modifying agents.


Antenatal and postnatal findings in encephalocraniocutaneous lipomatosis.
Encephalocraniocutaneous lipomatosis (ECCL) is a congenital neurocutaneous syndrome that comprises unilateral porencephalic cysts with cortical atrophy; ipsilateral hamartomas of scalp, eyelid, and outer part of the eye; lipomas of the central nervous system (CNS); cranial asymmetry; and characteristic cutaneous lesions. We report on the antenatal and postnatal sonographic and radiologic, and on the postnatal pathologic findings of an infant diagnosed with ECCL at birth. The antenatal sonogram at 28 weeks of gestation showed normal intracranial structures; the sonogram at 38 weeks of gestation showed asymmetry of the cerebral hemispheres and ventriculomegaly. Magnetic resonance imaging at age 6 weeks demonstrated a porencephalic cyst on the left, hemiatrophy of the left cerebrum with cortical dystrophy, and a lipoma in the middle cranial fossa. Histologic findings of the resected cutaneous lesion confirmed the presence of fibrolipoma hamartoma. This case offers a unique insight into the antenatal and postnatal development of the hamartoneoplastic lesions of ECCL, and it highlights the difficulties inherent in the antenatal sonographic diagnosis of hamartoneoplastic syndromes.


Nucleosomes and DNA methylation shape meiotic DSB frequency in Arabidopsis thaliana transposons and gene regulatory regions.
Meiotic recombination initiates from DNA double-strand breaks (DSBs) generated by SPO11 topoisomerase-like complexes. Meiotic DSB frequency varies extensively along eukaryotic chromosomes, with hotspots controlled by chromatin and DNA sequence. To map meiotic DSBs throughout a plant genome, we purified and sequenced Arabidopsis thaliana SPO11-1-oligonucleotides. SPO11-1-oligos are elevated in gene promoters, terminators, and introns, which is driven by AT-sequence richness that excludes nucleosomes and allows SPO11-1 access. A positive relationship was observed between SPO11-1-oligos and crossovers genome-wide, although fine-scale correlations were weaker. This may reflect the influence of interhomolog polymorphism on crossover formation, downstream from DSB formation. Although H3K4me3 is enriched in proximity to SPO11-1-oligo hotspots at gene 5' ends, H3K4me3 levels do not correlate with DSBs. Repetitive transposons are thought to be recombination silenced during meiosis, to prevent nonallelic interactions and genome instability. Unexpectedly, we found high SPO11-1-oligo levels in nucleosome-depleted Helitron/Pogo/Tc1/Mariner DNA transposons, whereas retrotransposons were coldspots. High SPO11-1-oligo transposons are enriched within gene regulatory regions and in proximity to immunity genes, suggesting a role as recombination enhancers. As transposon mobility in plant genomes is restricted by DNA methylation, we used the met1 DNA methyltransferase mutant to investigate the role of heterochromatin in SPO11-1-oligo distributions. Epigenetic activation of meiotic DSBs in proximity to centromeres and transposons occurred in met1 mutants, coincident with reduced nucleosome occupancy, gain of transcription, and H3K4me3. Together, our work reveals a complex relationship between chromatin and meiotic DSBs within A. thaliana genes and transposons, with significance for the diversity and evolution of plant genomes.


Peripheral and splanchnic indole and oxindole levels in cirrhotic patients: a study on the pathophysiology of hepatic encephalopathy.
Intestinal bacteria metabolize tryptophan into indole, which is then further metabolized into oxindole, a sedative compound putatively involved in the pathophysiology of hepatic encephalopathy (HE). The aim of this study was to measure indole and oxindole levels in patients with cirrhosis with or without HE and to establish whether an intestinal production and a hepatic metabolism of these substances exist. We studied 10 healthy subjects (controls) and 51 cirrhotic patients: 17 without HE, 14 with a minimal HE, 8 with overt HE, and 12 who had undergone a transjugular intrahepatic portosystemic shunt (TIPS) procedure. In the last group, blood was collected from the artery, and the portal and hepatic veins during TIPS construction and from the peripheral veins before, immediately after, and at weekly intervals during the first month after TIPS. Plasma indole levels were significantly higher in patients with overt HE. Oxindole levels were higher in cirrhotics than in controls. Indole and ammonia were significantly correlated (r=0.66). Peripheral and splanchnic determinations showed that indole was produced in the intestine and cleared by the liver, similar to ammonia. TIPS implantation increased both indole and ammonia levels. After TIPS, the psychometric performance worsened in 4 of the 12 patients. The increase in indole plasma concentrations in these four patients was higher than in those who remained stable after undergoing TIPS. Indole correlates with HE and has a significant intestinal production and hepatic extraction; its level increases after TIPS and is related to psychometric performance. These data suggest that indole may be involved in the pathophysiology of HE.


Quantitative fluorescence resonance energy transfer (FRET) measurement with acceptor photobleaching and spectral unmixing.
Fluorescence resonance energy transfer (FRET) by acceptor photobleaching is a simple but effective tool for measurements of protein-protein interactions. Until recently, it has been restricted to qualitative or relative assessments owing to the spectral bleed-through contamination resulting from fluorescence overlap between the donor and the acceptor. In this paper, we report a quantitative algorithm that combines the spectral unmixing technique with FRET by acceptor photobleaching. By spectrally unmixing the emissions before and after photobleaching, it is possible to resolve the spectral bleed-through and retrieve the FRET efficiency/interaction distance quantitatively. Using a human keratinocyte cell line transfected with cyan fluorescent protein (CFP)- and yellow fluorescent protein (YFP)-tagged Cx26 connexins as an example, FRET information at homotypic gap junctions is measured and compared with well-established methods. Results indicate that the new approach is sensitive, flexible, instrument independent and solely FRET dependent. It can achieve FRET estimations similar to that from a sensitized emission FRET method. This approach has a great advantage in providing the relative concentrations of the donor and the acceptor; this is, for example, very important in the comparative study of cell populations with variable expression levels.


Quantitative MRI in refractory temporal lobe epilepsy: relationship with surgical outcomes.
Medically intractable temporal lobe epilepsy (TLE) remains a serious health problem. Across treatment centers, up to 40% of patients with TLE will continue to experience persistent postoperative seizures at 2-year follow-up. It is unknown why such a large number of patients continue to experience seizures despite being suitable candidates for resective surgery. Preoperative quantitative MRI techniques may provide useful information on why some patients continue to experience disabling seizures, and may have the potential to develop prognostic markers of surgical outcome. In this article, we provide an overview of how quantitative MRI morphometric and diffusion tensor imaging (DTI) data have improved the understanding of brain structural alterations in patients with refractory TLE. We subsequently review the studies that have applied quantitative structural imaging techniques to identify the neuroanatomical factors that are most strongly related to a poor postoperative prognosis. In summary, quantitative imaging studies strongly suggest that TLE is a disorder affecting a network of neurobiological systems, characterized by multiple and inter-related limbic and extra-limbic network abnormalities. The relationship between brain alterations and postoperative outcome are less consistent, but there is emerging evidence suggesting that seizures are less likely to remit with surgery when presurgical abnormalities are observed in the connectivity supporting brain regions serving as network nodes located outside the resected temporal lobe. Future work, possibly harnessing the potential from multimodal imaging approaches, may further elucidate the etiology of persistent postoperative seizures in patients with refractory TLE. Furthermore, quantitative imaging techniques may be explored to provide individualized measures of postoperative seizure freedom outcome.


Unveiling the foveal blue scotoma through an afterimage.
The absence of short-wave-sensitive (S-) cones in the human foveola normally goes unnoticed, but the resulting foveal S-cone, or blue, scotoma can be visualized as the negative afterimage of a short-wavelength adapting field on a larger white background. The afterimage has an annular shape with a lighter inner region that corresponds to Maxwell's spot, and a small bright spot in the center corresponding to the foveal blue scotoma. We have shown that the visibility of the center spot in the afterimage approximately follows the spectral sensitivity curve of the S-cones. We further demonstrate that the central bright spot subtends a retinal area that is coincident with the tritanopic region of the foveola. The macular pigment distribution measured for the same observers also peaks in the central fovea, but has a relatively high density over a broader retinal region than the bright spot in the negative afterimage, and more closely corresponds to the lighter annular region of the afterimage. The results support the hypothesis of an active post-receptoral process for filling-in of chromatic scotomas.


Copying of Mixed-Sequence RNA Templates inside Model Protocells.
The chemical replication of RNA inside fatty acid vesicles is a plausible step in the emergence of cellular life. On the primitive Earth, simple protocells with the ability to import nucleotides and short oligomers from their environment could potentially have replicated and retained larger genomic RNA oligonucleotides within a spatially defined compartment. We have previously shown that short 5'-phosphoroimidazolide-activated "helper" RNA oligomers enable the nonenzymatic copying of mixed-sequence templates in solution, using 5'-phosphoroimidazolide-activated mononucleotides. Here, we report that citrate-chelated Mg2+, a catalyst of nonenzymatic primer extension, enhances fatty acid membrane permeability to such short RNA oligomers up to the size of tetramers, without disrupting vesicle membranes. In addition, selective permeability of short, but not long, oligomers can be further enhanced by elevating the temperature. The ability to increase the permeability of fatty acid membranes to short oligonucleotides allows for the nonenzymatic copying of RNA templates containing all four nucleotides inside vesicles, bringing us one step closer to the goal of building a protocell capable of Darwinian evolution.


Taxonomy of the feline mycoplasmas Mycoplasma felifaucium, Mycoplasma feliminutum, Mycoplasma felis, Mycoplasma gateae, Mycoplasma leocaptivus, Mycoplasma leopharyngis, and Mycoplasma simbae by 16S rRNA gene sequence comparisons.
The nucleotide sequence of the 16S rRNA gene of eight mycoplasmas isolated from felids was determined and used for taxonomic comparisons. A signature nucleotide sequence motif and overall sequence similarity to other mollicutes positioned Mycoplasma felifaucium, Mycoplasma felis, Mycoplasma leocaptivus, Mycoplasma leopharyngis, and Mycoplasma simbae in the Mycoplasma fermentans phylogenetic group of mollicutes. Mycoplasma arginini and Mycoplasma gateae were positioned in the Mycoplasma hominis phylogenetic group of mollicutes, and Mycoplasma feliminutum was positioned in the phylogenetically distant Acholeplasma group of mollicutes, showing that host family preference does not necessarily derive from bacterial phylogenetic closeness.


Under-arm partial body weight unloading causes spinal elongation and vibration attenuation during treadmill walking.
Whilst exercise is beneficial to those suffering from low back pain (LBP), spinal shrinkage and vibration during walking may aggravate the condition. This study investigates the effects of spinal unloading, by means of body-weight unloading (BWU), on spinal length and vibration response. Under-arm partial BWU (40% of bodyweight) was performed on 8 healthy males whilst walking on a treadmill for 1h, and compared to a control condition in the same participants. Motion analysis was used to track four reflective markers attached to the spine between C7 and the lumbar concavity at 100Hz, in 7s samples at regular intervals during the walk. A quintic polynomial was fitted to the coordinates in the sagittal plane, and sub-sectioned into three regions: the upper thoracic (UT), lower thoracic (LT) and upper lumbar (UL). The lengths of the curves were analysed in the time and frequency domains. The length of the spine increased by 4+/-2% (18mm) during the unloading condition with all regions showing an increase in length. The UL and LT regions lost length in the control condition, thereby exhibiting a significant interaction between unloading and time on region length (both P<0.05). In addition, compared to the control condition, the frequencies of the length changes were attenuated between 3 and 6Hz with unloading. Therefore, under-arm BWU facilitates spinal elongation, attenuates the frequency response of the spine in its resonant frequency regime and thus has potential benefits to the LBP population.


Stereoselective disposition of hydratropic acid in rat.
The stereoselective distribution, metabolism, and excretion of 2-phenylpropionic acid (hydratropic acid, HTA) was studied by giving racemic HTA (20 mg/kg) to intact, bile duct-cannulated, bile duct-ligated, and nephrectomized and bile duct-cannulated rats. In intact rats, the percentage of (R)-(-)-HTA in plasma was 53%, but 46-48% in various tissues at 5 min after dosing. A slightly higher binding affinity of (R)-(-)-HTA to plasma protein than the (S)-(+) form should be one of the important factors controlling the enrichment of (S)-(+)-HTA percentage in tissues and the increase of (R)-(-)-HTA percentage in plasma shortly after administration of racemate. About 66% of the dose was excreted in urine of intact rats (HTA acyl glucuronide (HTA-G): 54%; HTA: 12%) in 8 hr. Bile duct-cannulated rats excreted about 51% of the dose in bile as HTA-G and 40% in urine (HTA-G: 32%; HTA: 8%) in 6 hr. The (R)-(-)-enantiomer percentage of biliary HTA-G was about 25%, urinary HTA-G was 45%, and HTA was 57%. Since about 63% of the dose was excreted in bile and urine as the (S)-(+)-enantiomer after injection of racemate to bile duct-cannulated rats, stereoselective isomerization of (R)-(-)-HTA to the (S)-(+) form is suggested. The (R)-(-)-enantiomer percentage of HTA-G in urine decreased with ligation of the bile duct, but that of the HTA-G in 0-30-min bile was not influenced by nephrectomy. These results suggest that the step regulating stereoselective excretion of HTA-G in rats is that of its excretion from the liver into bile and blood. There should be no or very little stereoselectivity in the step of HTA-G excretion through the kidney into the urine.


A unified framework for image retrieval using keyword and visual features.
In this paper, a unified image retrieval framework based on both keyword annotations and visual features is proposed. In this framework, a set of statistical models are built based on visual features of a small set of manually labeled images to represent semantic concepts and used to propagate keywords to other unlabeled images. These models are updated periodically when more images implicitly labeled by users become available through relevance feedback. In this sense, the keyword models serve the function of accumulation and memorization of knowledge learned from user-provided relevance feedback. Furthermore, two sets of effective and efficient similarity measures and relevance feedback schemes are proposed for query by keyword scenario and query by image example scenario, respectively. Keyword models are combined with visual features in these schemes. In particular, a new, entropy-based active learning strategy is introduced to improve the efficiency of relevance feedback for query by keyword. Furthermore, a new algorithm is proposed to estimate the keyword features of the search concept for query by image example. It is shown to be more appropriate than two existing relevance feedback algorithms. Experimental results demonstrate the effectiveness of the proposed framework.


Anti-fibrotic Actions of Roselle Extract in Rat Model of Myocardial Infarction.
Heart failure-associated morbidity and mortality is largely attributable to extensive and unregulated cardiac remodelling. Roselle (Hibiscus sabdariffa) calyces are enriched with natural polyphenols known for antioxidant and anti-hypertensive effects, yet its effects on early cardiac remodelling in post myocardial infarction (MI) setting are still unclear. Thus, the aim of this study was to investigate the actions of roselle extract on cardiac remodelling in rat model of MI. Male Wistar rats (200-300 g) were randomly allotted into three groups: Control, MI, and MI + Roselle. MI was induced with isoprenaline (ISO) (85 mg/kg, s.c) for two consecutive days followed by roselle treatment (100 mg/kg, orally) for 7 days. Isoprenaline administration showed changes in heart weight to body weight (HW/BW) ratio. MI was especially evident by the elevated cardiac injury marker, troponin-T, and histological observation. Upregulation of plasma levels and cardiac gene expression levels of inflammatory cytokines such as interleukin (IL)-6 and IL-10 was seen in MI rats. A relatively high percentage of fibrosis was observed in rat heart tissues with over-expression of collagen (Col)-1 and Col-3 genes following isoprenaline-induced MI. On top of that, cardiomyocyte areas were larger in heart tissues of MI rats with upregulation of atrial natriuretic peptide (ANP) and brain natriuretic peptide (BNP) gene expression, indicating cardiac hypertrophy. Interestingly, roselle supplementation attenuated elevation of plasma troponin-T, IL-6, IL10, and gene expression level of IL-10. Furthermore, reduction of cardiac fibrosis and hypertrophy were observed. In conclusion, roselle treatment was able to limit early cardiac remodelling in MI rat model by alleviating inflammation, fibrosis, and hypertrophy; hence, the potential application of roselle in early adjunctive treatment to prevent heart failure.


Genetically encoded green fluorescent Ca2+ indicators with improved detectability for neuronal Ca2+ signals.
Imaging the activities of individual neurons with genetically encoded Ca(2+) indicators (GECIs) is a promising method for understanding neuronal network functions. Here, we report GECIs with improved neuronal Ca(2+) signal detectability, termed G-CaMP6 and G-CaMP8. Compared to a series of existing G-CaMPs, G-CaMP6 showed fairly high sensitivity and rapid kinetics, both of which are suitable properties for detecting subtle and fast neuronal activities. G-CaMP8 showed a greater signal (F(max)/F(min) = 38) than G-CaMP6 and demonstrated kinetics similar to those of G-CaMP6. Both GECIs could detect individual spikes from pyramidal neurons of cultured hippocampal slices or acute cortical slices with 100% detection rates, demonstrating their superior performance to existing GECIs. Because G-CaMP6 showed a higher sensitivity and brighter baseline fluorescence than G-CaMP8 in a cellular environment, we applied G-CaMP6 for Ca(2+) imaging of dendritic spines, the putative postsynaptic sites. By expressing a G-CaMP6-actin fusion protein for the spines in hippocampal CA3 pyramidal neurons and electrically stimulating the granule cells of the dentate gyrus, which innervate CA3 pyramidal neurons, we found that sub-threshold stimulation triggered small Ca(2+) responses in a limited number of spines with a low response rate in active spines, whereas supra-threshold stimulation triggered large fluorescence responses in virtually all of the spines with a 100% activity rate.


Receptive-field characteristics of neurons in cat striate cortex: Changes with visual field eccentricity.
1. Receptive-field properties of 214 neurons from cat striate cortex were studied with particular emphasis on: a) classification, b) field size, c) orientation selectivity, d) direction selectivity, e) speed selectivity, and f) ocular dominance. We studied receptive fields located throughtout the visual field, including the monocular segment, to determine how receptivefield properties changed with eccentricity in the visual field.2. We classified 98 cells as "simple," 80 as "complex," 21 as "hypercomplex," and 15 in other categories. The proportion of complex cells relative to simple cells increased monotonically with receptive-field eccenticity.3. Direction selectivity and preferred orientation did not measurably change with eccentricity. Through most of the binocular segment, this was also true for ocular dominance; however, at the edge of the binocular segment, there were more fields dominated by the contralateral eye.4. Cells had larger receptive fields, less orientation selectivity, and higher preferred speeds with increasing eccentricity. However, these changes were considerably more pronounced for complex than for simple cells.5. These data suggest that simple and complex cells analyze different aspects of a visual stimulus, and we provide a hypothesis which suggests that simple cells analyze input typically from one (or a few) geniculate neurons, while complex cells receive input from a larger region of geniculate neurons. On average, this region is invariant with eccentricity and, due to a changing magnification factor, complex fields increase in size with eccentricity much more than do simple cells. For complex cells, computations of this geniculate region transformed to cortical space provide a cortical extent equal to the spread of pyramidal cell basal dendrites.


The temporal changes of tissue oxygen saturation (StO2) and central venous oxygen saturation (ScvO2) during sepsis/septic shock resuscitation.
Restoration of adequate tissue oxygenation is the goal of shock resuscitation. Commonly, central venous oxygen saturation and lactate clearance are used to monitor this therapeutic endpoint in sepsis. Tissue oxygen saturation (StO2) obtained by near-infrared spectroscopy (NIRS) has been introduced as an alternative. To determine the temporal changes of tissue oxygen saturation and central venous oxygen saturation (ScvO2) in severe sepsis/septic shock patients from initial resuscitation to 72 hours after treatment, and to explore the relationship between both parameters including the association with outcomes. A prospective, observational study was performed in a single center 14-bed university hospital, Medical Intensive Care Unit. The present study enrolled severe sepsis/septic shock patients aged > 18 years. Central venous oxygen saturation and tissue oxygen saturation were measured at 0-1st hour (right after central venous catheter was placed), 1st-6th hour (the point when hemodynamic goal was achieved), 6th-9th hour 9th-12th hour 24th hour, 48th hour, and 72th hour in simultaneous fashion. Thirty-five patients were enrolled and 170 paired-measurements were made. During the first 24 hours, both tissue and central venous oxygen saturation gradually increased in the same direction. However only fair correlation was observed (r = 0.253, p = 0.01) and the agreement was not satisfactory. Mean StO2 during the first 24 hours was higher in survived patients ((82.6 +/- 9.3 vs. 74.3 +/- 16.0, p = 0.016). When partitioned ScvO2 into ranges, namely ScvO2 < 60%, 60-64%, 65-69%, 70-74%, 75-79%, 80-84% and > 85%, the corresponding StO2 values were found randomly throughout the ScvO2 ranges, without specific predilection. The temporal changes of StO2 and ScvO2 during sepsis/septic shock resuscitation were demonstrated. Their correlation and agreement were not satisfactory. No specific StO2 value for the reversal of tissue hypoxia was observed. More studies are needed to explore the benefit of StO2 as a bedside tool for tissue perfusion monitoring.


An Adaptive Imitation Learning Framework for Robotic Complex Contact-Rich Insertion Tasks.
Complex contact-rich insertion is a ubiquitous robotic manipulation skill and usually involves nonlinear and low-clearance insertion trajectories as well as varying force requirements. A hybrid trajectory and force learning framework can be utilized to generate high-quality trajectories by imitation learning and find suitable force control policies efficiently by reinforcement learning. However, with the mentioned approach, many human demonstrations are necessary to learn several tasks even when those tasks require topologically similar trajectories. Therefore, to reduce human repetitive teaching efforts for new tasks, we present an adaptive imitation framework for robot manipulation. The main contribution of this work is the development of a framework that introduces dynamic movement primitives into a hybrid trajectory and force learning framework to learn a specific class of complex contact-rich insertion tasks based on the trajectory profile of a single task instance belonging to the task class. Through experimental evaluations, we validate that the proposed framework is sample efficient, safer, and generalizes better at learning complex contact-rich insertion tasks on both simulation environments and on real hardware.


Klotho coreceptors inhibit signaling by paracrine fibroblast growth factor 8 subfamily ligands.
It has been recently established that Klotho coreceptors associate with fibroblast growth factor (FGF) receptor tyrosine kinases (FGFRs) to enable signaling by endocrine-acting FGFs. However, the molecular interactions leading to FGF-FGFR-Klotho ternary complex formation remain incompletely understood. Here, we show that in contrast to αKlotho, βKlotho binds its cognate endocrine FGF ligand (FGF19 or FGF21) and FGFR independently through two distinct binding sites. FGF19 and FGF21 use their respective C-terminal tails to bind to a common binding site on βKlotho. Importantly, we also show that Klotho coreceptors engage a conserved hydrophobic groove in the immunoglobulin-like domain III (D3) of the "c" splice isoform of FGFR. Intriguingly, this hydrophobic groove is also used by ligands of the paracrine-acting FGF8 subfamily for receptor binding. Based on this binding site overlap, we conclude that while Klotho coreceptors enhance binding affinity of FGFR for endocrine FGFs, they actively suppress binding of FGF8 subfamily ligands to FGFR.


Posterior reversible encephalopathy syndrome in an adult patient undergoing peritoneal dialysis: a case report and literature review.
Posterior reversible encephalopathy syndrome (PRES) is a clinical and radiological entity characterized clinically by headache, altered mental status, seizures, visual disturbances, and other focal neurological signs, and radiographically by reversible changes on imaging. A variety of different etiologies have been reported, but the underlying mechanism is thought to be failed cerebral autoregulation. To the best of our knowledge, we report the third known case of PRES in an adult receiving intermittent peritoneal dialysis (PD). A 23-year-old male receiving PD was brought to hospital after experiencing a generalized seizure. On presentation he was confused and hypertensive. An MRI brain was obtained and showed multiple regions of cortical and subcortical increased T2 signal, predominantly involving the posterior and paramedian parietal and occipital lobes with relative symmetry, reported as being consistent with PRES. A repeat MRI brain obtained three months later showed resolution of the previous findings. Due to having a large number of endothelium-disrupting risk factors, including hypertension, uremia, and medications known to disrupt the cerebrovascular endothelium, we suggest that those with end-stage renal disease (ESRD) receiving PD are at high risk of developing PRES. Furthermore, we surmise that PRES is likely more prevalent in the ESRD population but is under recognized. Physicians treating those with ESRD must have a high index of suspicion of PRES in patients presenting with neurological disturbances to assure timely diagnosis and treatment.


Myelofibrosis with myeloid metaplasia: diagnostic definition and prognostic classification for clinical studies and treatment guidelines.
Myelofibrosis with myeloid metaplasia (MMM) is a chronic myeloproliferative disorder characterized by bone marrow fibrosis and extramedullary hematopoiesis. Recent studies provide definite diagnostic criteria and prognostic classifications of the disease, and allogeneic stem-cell transplantation (SCT) now offers a chance of curing the disease. In order to put diagnostic criteria and prognostic classifications of the disease into the perspective of developing guidelines for treatment strategies, all studies published in the English literature over the last 30 years were reviewed. Studies were identified through a MEDLINE search (1966 to present) and from the bibliographies of relevant articles. The Italian Consensus Conference on diagnostic criteria is a structured enterprise aimed at formulating a definition of MMM that will be used for enrolling patients onto clinical studies. It relies on the obligatory presence of myelofibrosis and on the exclusion of the BCR-ABL rearrangement or Philadelphia chromosome, in association with combinations of traditional features. Prognostic scores allow us to identify classes of patients on the basis of hemoglobin, age, WBC count, and chromosomal abnormalities. Several nonrandomized studies have indicated that allogeneic SCT for patients under the age of 55 is effective in prolonging survival in more than 50% of cases and in possibly curing the disease. Patients with the most severe prognosis are candidates. "Consensus" methodology offers a definition of MMM useful for conducting and reporting clinical studies. A detailed knowledge of prognostic factors can help to delineate guidelines for addressing patients with allogeneic SCT.


Neuroprotective effect of NMDA receptor glycine recognition site antagonism persists when brain temperature is controlled.
Several lines of inquiry have indicated that glycine plays an important role in both glutamatergic neurotransmission and pathophysiology of cerebral ischemia. However, subacute outcome trials demonstrating the efficacy of glycine antagonists as neuroprotectants have not been performed with rigorous control of brain temperature. In this study, we investigated the effect of N-methyl-D-aspartate (NMDA) receptor glycine recognition site antagonism in a temperature-controlled rodent model of transient focal ischemia. Male Wistar rats underwent 75 min of intraluminal middle cerebral artery occlusion (MCAO). During MCAO and the first 24 h of reperfusion, rats (n = 10) were administered e55-nitro-6,7-dichloro-2,3-quinoxalinedione (ACEA 1021) i.v. as a bolus infusion of 5 mg/kg followed by 3.5 mg/kg/h (Low-Dose) or 10 mg/kg followed by 7 mg/kg/ h (High-Dose) for 24 h. Cortical temperature was controlled at 38.0 +/- 0.1 degrees C during MCAO and the first 6 h of reperfusion. A 7-day recovery interval was allowed. Mean total infarct volume was reduced by approximately 40% in both high- and low-dose groups (p < 0.01). The preponderance of infarct reduction occurred in the cortex (p < 0.01). Neurologic function correlated with the size of cerebral infarct (p = 0.001). Neurologic grade was similarly improved by treatment with either dose (p = 0.01). These results demonstrate that neuroprotection achieved by antagonism of the glycine recognition site persists when brain temperature is controlled, indicating a potent mechanism of action other than attenuating a hyperthermic response to ischemia.


Maintenance of a normal meal-induced decrease in plasma ghrelin levels in children with Prader-Willi syndrome.
Ghrelin is a 28-amino acid peptide recently identified in the stomach as the endogenous ligand for the growth hormone secretagogue receptor (GHS-R1a). Ghrelin is a potent stimulator of GH secretion. It was recently shown that circulating ghrelin levels in humans rise shortly before and fall shortly after every meal, and that ghrelin administration increases voluntary food intake. The hypothesis that ghrelin hypersecretion might contribute to genetic obesity has never been investigated. In this context, Prader-Willi syndrome is the most common form of human syndromic obesity. As ghrelin affects appetite as well as GH secretion and both are abnormal in PWS, it has been surmised that these alterations might be due to ghrelin dysregulation. The aim of the study was to investigate whether ghrelin is suppressed by the meals differently in PWS children than in PWS adults. Overnight circulating fasting ghrelin levels and ghrelin levels 120 min after breakfast were assayed in 7 PWS children (10.2 +/- 1.7 yr), 7 subjects with morbid obesity (10.3 +/- 1.3 yr), and 5 normal controls (8.4 +/- 1.4 yr). Because of the data spread, no statistical difference was observed in fasting ghrelin levels between PWS and control children (p = NS); anyway, fasting ghrelin levels were significantly lower in obese children than in the other groups (p < 0.05 vs. control and PWS children). Ghrelin levels were slightly suppressed by the meal in control subjects (mean fasting ghrelin: 160.2 +/- 82 pg/ml; after the meal, 141.2 +/- 57 pg/ml, p = NS); the meal failed to suppress ghrelin levels in obese children (mean fasting ghrelin: 126.4 +/- 8.5 pg/ml; after the meal, 119.1 +/- 8.3 pg/ml, p = NS). Interestingly, the meal markedly suppressed ghrelin levels in PWS children (mean fasting ghrelin: 229.5 +/- 70.4 pg/ml; after the meal, 155.8 +/- 34.2 pg/ml, p < 0.01). In conclusion, since a lack of decrease in circulating ghrelin induced by the meal was previously reported in PWS adults, the finding of a meal-induced decrease in ghrelin levels in our population of young PWS would imply that the regulation of the ghrelin system involved in the orexigenic effects of the peptide is operative during childhood, although it progressively deteriorates and is absent in adulthood when hyperphagia and obesity progressively worsen.


The Port Pirie cohort study: maternal blood lead and pregnancy outcome.
During a three-year period, 831 pregnant women in and around Port Pirie, South Australia--a lead smelter community with longstanding lead pollution--were enrolled in a cohort study to examine prospectively the relation between body lead burden and pregnancy outcome. Three-quarters of the enrolled women were residents of the Port Pirie municipality; the other women lived in adjacent towns and countryside. At 14-20 weeks' gestation, the Port Pirie resident women had a mean blood lead concentration of 10.6 micrograms/dl, while the mean in the other (non-Port Pirie) women was 7.6 micrograms/dl. Similar differences were observed in maternal blood samples taken at 30-36 weeks, at delivery, and from the umbilical cord. These blood lead measures, in conjunction with information collected on other risk factors, were then examined in relation to pregnancy outcome. Among 749 pregnancies followed to completion, pre-term delivery was statistically significantly associated, in a dose-response manner, with maternal blood lead concentration at delivery. Mothers of late fetal deaths (stillbirths) had blood lead concentrations at 14-20 weeks' gestation similar to those of all the other women but had lower concentrations at delivery than the other women. Outcomes of pregnancy for which no association with blood lead was detected were spontaneous abortion, low birthweight (for births at term), intrauterine growth retardation, premature rupture of the membranes, and congenital anomalies.


Measures and predictors of community-based employment and earnings of persons with schizophrenia in a multisite study.
Data from a national study of persons with schizophrenia-related disorders were examined to determine clinical factors and labor-market conditions related to employment outcomes. Data were obtained from the U.S. Schizophrenia Care and Assessment Program, a naturalistic study of more than 2,300 persons from organized care systems in six U.S. regions. Data were collected via surveys and from medical records and clinical assessments at baseline and for three years. Outcome measures included any community-based (nonsheltered) employment, 40 or more hours of work in the past month, employment at or above the federal minimum wage, days and hours of work, and earnings. Bivariate and multiple regression analyses of data from more than 7,000 assessments tested relationships between outcomes and sociodemographic, clinical, and local labor market characteristics. The employment rate was 17.2%; only 57.1% of participants who worked reported 40 or more hours of past-month employment. The mean hourly wage was $7.05, and mean monthly earnings were $494.20. Employment rates and number of hours worked were substantially below those found in household surveys or in baseline data from trials of employment programs but substantially higher than those found in a recent large clinical trial. Strong positive relationships were found between clinical factors and work outcomes, but evidence of a relationship between local unemployment rates and outcomes was weak. Work attachment and earnings were substantially lower than in previous survey data, not very sensitive to labor market conditions, and strongly related to clinical status.


[Historical evolution of some clinical and epidemiological knowledge of coccidioidomycosis in the Americas].
Coccidioidomycosis is a systemic endemic mycosis caused by two dimorphic fungi of the Coccidioides genus: Coccidioides immitis and Coccidioides posadasii. This fungal infection is only endemic in the American Continent. The majority of the epidemiological, pathogenic, clinical, mycological and therapeutical findings were obtained in the U.S.A. Coccidioidomycosis was discovered in Argentina, at the end of the XIXth century by Alejandro Posadas. In the last two decades, a new endemic zone was found in the northeast of Brazil. Several countries of the region such as Mexico, Guatemala, Honduras, Venezuela and Argentina have performed epidemiological studies which allowed a better knowledge of the endemic areas and of the clinical characteristics of this mycosis.


Exposure to dairy manure leads to greater antibiotic resistance and increased mass-specific respiration in soil microbial communities.
Intensifying livestock production to meet the demands of a growing global population coincides with increases in both the administration of veterinary antibiotics and manure inputs to soils. These trends have the potential to increase antibiotic resistance in soil microbial communities. The effect of maintaining increased antibiotic resistance on soil microbial communities and the ecosystem processes they regulate is unknown. We compare soil microbial communities from paired reference and dairy manure-exposed sites across the USA. Given that manure exposure has been shown to elicit increased antibiotic resistance in soil microbial communities, we expect that manure-exposed sites will exhibit (i) compositionally different soil microbial communities, with shifts toward taxa known to exhibit resistance; (ii) greater abundance of antibiotic resistance genes; and (iii) corresponding maintenance of antibiotic resistance would lead to decreased microbial efficiency. We found that bacterial and fungal communities differed between reference and manure-exposed sites. Additionally, the β-lactam resistance gene ampC was 5.2-fold greater under manure exposure, potentially due to the use of cephalosporin antibiotics in dairy herds. Finally, ampC abundance was positively correlated with indicators of microbial stress, and microbial mass-specific respiration, which increased 2.1-fold under manure exposure. These findings demonstrate that the maintenance of antibiotic resistance associated with manure inputs alters soil microbial communities and ecosystem function.


Return to official Italian First Division soccer games within 90 days after anterior cruciate ligament reconstruction: a case report.
Case report. To present the rehabilitative course, decision-making, and clinical milestones that allowed a top-level professional soccer player to return to full competitive activity 90 days after surgery. The patient was a 35-year-old forward player who sustained an isolated complete tear of the left anterior cruciate ligament (ACL) in the midst of the competitive 2001-2002 season. He was in contention for a position on the Italian World Cup Team that was to be played 135 days after his injury, only if he demonstrated that he could return to play at the highest level before the team was selected. The patient underwent an arthroscopically assisted ACL reconstruction with a double-loop semitendinosus-gracilis autograft 4 days after the injury. Eight days after surgery he began rehabilitation at a rate of 2 sessions a day, 5 days a week, plus 1 session every Saturday morning. These sessions were performed in a pool for aquatic exercises, in a gymnasium for flexibility, coordination, and strength exercises, and on a soccer field for recovery of technical and tactical skills, with continuous monitoring of training intensity. The surgical technique and the progressive rehabilitation program allowed the patient to play for 20 minutes in an official First Division soccer game 77 days after surgery and to play a full game 90 days after surgery. Eighteen months postsurgery, the player had participated in 62 First Division matches, scoring 26 times, and had received no further treatment for his knee. This case report suggests that early return to high-level competition after ACL reconstruction is possible in some instances. Some factors that may have favored the early return include optimal physical fitness before surgery, a strong psychological determination, an isolated ACL lesion, a properly placed and tensioned graft, a personalized progression of volume and intensity of exercise loads, and an appropriate density of rehabilitative training consisting of a mix of gymnasium, pool, and field exercises.


Knowledge and conscious control of motor actions under stress.
A recent study by Masters (1992) investigated the effect of stress upon the performance of a well-learned motor skill, golf putting, acquired under implicit and explicit learning conditions. Masters found that stress had a detrimental effect on performance for the explicit learning group but not for the implicit learning group. However, the implicit learning group was required to perform articulatory suppression during the learning trials but not during the stress trials. As such, it is possible that the subjects in the implicit learning group continued to improve during the stress session simply because they were performing an easier task. This paper reports an experiment which re-examines Masters' (1992) conclusions by replicating and extending his method. An additional implicit learning group was included which was required to carry out articulatory suppression during both the learning trials and the stress trials. It was hypothesized that this 'new' implicit learning group would suffer the same disruption to performance as the explicit learning group, providing evidence which would contradict Masters' explanation. Thirty-two subjects were allocated to one of four groups. Performance measures were analysed using two-factor analysis of variance (4 x 5: groups x sessions) with repeated measures on the sessions factor. The main dependent variable was the number of putts successfully completed. The analysis revealed that both the implicit learning groups continued to improve their performance under stress whilst the explicit learning group did not. Despite limitations to both Masters' (1992) and the present study, these results add support to Masters' explicit knowledge hypothesis.


Fluorescence labeled microbubbles for multimodal imaging.
Air-filled polyvinyl alcohol microbubbles (PVA-MBs) were recently introduced as a contrast agent for ultrasound imaging. In the present study, we explore the possibility of extending their application in multimodal imaging by labeling them with a near infrared (NIR) fluorophore, VivoTag-680. PVA-MBs were injected intravenously into FVB/N female mice and their dynamic biodistribution over 24 h was determined by 3D-fluorescence imaging co-registered with 3D-μCT imaging, to verify the anatomic location. To further confirm the biodistribution results from in vivo imaging, organs were removed and examined histologically using bright field and fluorescence microscopy. Fluorescence imaging detected PVA-MB accumulation in the lungs within the first 30 min post-injection. Redistribution to a low extent was observed in liver and kidneys at 4 h, and to a high extent mainly in the liver and spleen at 24 h. Histology confirmed PVA-MB localization in lung capillaries and macrophages. In the liver, they were associated with Kupffer cells; in the spleen, they were located mostly within the marginal-zone. Occasional MBs were observed in the kidney glomeruli and interstitium. The potential application of PVA-MBs as a contrast agent was also studied using ultrasound (US) imaging in subcutaneous and orthotopic pancreatic cancer mouse models, to visualize blood flow within the tumor mass. In conclusion, this study showed that PVA-MBs are useful as a contrast agent for multimodal imaging.


A new method for encapsulation of living cells: preliminary results with PC12 cell line.
A new method is described for encapsulation of living cells. PC12 rat adrenal pheochromocytoma cells, which have been shown to synthesize, store and release dopamine were employed. The particles are made first and the cells then incorporated in a gentle mechanical procedure. The morphology (by light and electron microscopic observation), stability, rheology, texture and permeability of these microcapsules provided by Kappa Biotech were investigated. Membrane permeability studies demonstrated exclusion of 69,000 Da human serum albumin, but equilibrium of D-glucose and inulin was within 24h, indicating a molecular weight cut-off in the 5000-70,000 Da range. The viability and the function of the encapsulated cells were evaluated by measuring the spontaneous release of dopamine by high performance liquid chromatography with electrochemical detection. The results show that dopamine-secreting cells can be sequestered in a semi-permeable capsule and still display good viability and proliferation for at least 1 month.


Malpractice claims and unintentional outcome of tonsil surgery and other standard procedures in otorhinolaryngology.
Septoplasty, tonsillectomy (with and without adenoidectomy) and cervical lymph node excision are amongst the most common 50 inpatient operations in Germany. Intracapsular tonsillectomies (i.e. tonsillotomies) are increasingly performed. The aim of this study was to evaluate technical traps and pitfalls as well as alleged medical malpractice associated with tonsillectomy (TE), adenoidectomy (AE), tonsillotomy (TT), septoplasty (SP) and cervical lymph node excision (LN). A questionnaire was sent to the Regional Medical Conciliation Boards, Medical Services of the Health Insurance Companies (MDK) and Regional Institutes of Forensic Medicine in Germany to collect anonymized cases of complications following TE, TT, AE, LN and SP. The results were discussed in the light of the contemporary medical literature and published trials and verdicts in Germany. The response rate of our survey was 55.9%. The Institutes of Forensic Medicine contributed nine cases, 49 cases were submitted by the Regional Conciliation Boards and none by MDK. All forensic cases were associated with exsanguinations following tonsillectomy including two children (5 and 8 years of age) and seven adults (aged 20 to 69 years). The fatal post-tonsillectomy hemorrhage (PTH) had occurred 8.7 days on average; four patients experienced the bleeding episode at home (day 5, 8, 9 and 17, respectively). Repeated episodes of bleeding requiring surgical intervention had occurred in 6 patients. Three Conciliation Boards submitted decicions associated with TT (1), AE (4), LN (3), SP (16) and TE (25). Cases with lethal outcome were not registered. Only three of the 49 cases were assessed as surgical malpractice (6.1%) including lesion of the spinal accessory nerve, wrong indication for TE and dental lesion after insertion of the mouth gag. The review of the medico legal literature yielded 71 published verdicts after AE and TE (29), LN (28) and SP (14) of which 37 resulted in compensation of malpractice after LN (16; 57%), TE (10; 37%), SP (8; 57%) and AE (2; 100%). There were 16 cases of PTH amongst 27 trials after TE resulting either in death (5) or apallic syndrome (5). Bleeding complications had occurred on the day of surgery in only 2 patients. 16 trials were based on malpractice claims following SP encompassing lack of informed consent (6), anosmia (4), septal perforation (2), frontobasal injury (2) and dry nose (2). Trials after LN procedures were associated exclusively with a lesion of the spinal accessory nerve (28), including lack of informed consent in 19 cases. 49 cases (69%) were decided for the defendant, 22 (31%) were decided for the plaintiff with monetary compensation in 7 of 29 AE/TE-trials, 9 of 28 LN-trials and 6 of 14 SP-trials. Lack of informed consent was not registered for AE/TE but LN (11) and SP (2). Complicated cases following TE, TT, ATE, SP and LN are not systematically collected in Germany. It can be assumed, that not every complicated case is published in the medical literature or law journals and therefore not obtainable for scientific research. Alleged medical malpracice is proven for less than 6% before trial stage. Approximately half of all cases result in a plaintiff verdict or settlement at court. Proper documentation of a thourough counselling, examination, indication, informed consent and follow-up assists the surgeon in litigation. An adequate complication management of PTH is essential, including instructions for the patients/parents, instructions for the medical staff and readily available surgical instruments. Successful outcome of life-threatening PTH is widely based on a proper airway management in an interdisciplinary approach. Electrosurgical tonsillectomy techniques were repeatedly labeled as a risk factor for bleeding complications following TE. Institutions should analyse the individual PTH rate on a yearly basis. Contradictory expert opinions and verdicts of the courts concerning spinal accesory nerve lesions following LN are due to a lack of a surgical standard.


A Randomized, Controlled Trial of the Impact of the Couple CARE for Parents of Newborns Program on the Prevention of Intimate Partner Violence and Relationship Problems.
Effective, accessible prevention programs are needed for adults at heightened risk for intimate partner violence (IPV). This parallel group randomized controlled trial examines whether such couples receiving the American version of Couple CARE for Parents of Newborns (CCP; Halford et al. 2009) following the birth of a child, compared with controls, report fewer first occurrences of clinically significant IPV, less frequent physical and psychological IPV, and improved relationship functioning. Further, we test whether intervention effects are moderated by level of risk for IPV. Couples at elevated risk for IPV (N = 368) recruited from maternity units were randomized to CCP (n = 188) or a 24-month waitlist (n = 180) and completed measures of IPV and relationship functioning at baseline, post-program (when child was 8 months old), and two follow-ups (at 15 and 24 months). Intervention effects were tested using intent to treat (ITT) as well as complier average causal effect (CACE; Jo and Muthén 2001) structural equation models. CCP did not significantly prevent clinically significant IPV nor were there significant main effects of CCP on clinically significant IPV, frequency of IPV, or most relationship outcomes in the CACE or ITT analyses. Risk moderated the effect of CCP on male-to-female physical IPV at post-program, with couples with a planned pregnancy declining, but those with unplanned pregnancies increasing. This study adds to previous findings that prevention programs for at-risk couples are not often effective and may even be iatrogenic for some couples.


Functionalisation of PLLA nanofiber scaffolds using a possible cooperative effect between collagen type I and BMP-2: impact on growth and osteogenic differentiation of human mesenchymal stem cells.
Mesenchymal stem cell differentiation of osteoblasts is triggered by a series of signaling processes including integrin and bone morphogenetic protein (BMP), which therefore act in a cooperative manner. The aim of this study was to analyze whether these processes can be remodeled in an artificial poly-(L)-lactide acid (PLLA) based nanofiber scaffold. Matrices composed of PLLA-collagen type I or BMP-2 incorporated PLLA-collagen type I were seeded with human mesenchymal stem cells (hMSC) and cultivated over a period of 22 days, either under growth or osteoinductive conditions. During the course of culture, gene expression of alkaline phosphatase (ALP), osteocalcin (OC) and collagen I (COL-I) as well as Smad5 and focal adhesion kinase (FAK), two signal transduction molecules involved in BMP-2 or integrin signaling were analyzed. Furthermore, calcium and collagen I deposition, as well as cell densities and proliferation, were determined using fluorescence microscopy. The incorporation of BMP-2 into PLLA-collagen type I nanofibers resulted in a decrease in diameter as well as pore sizes of the scaffold. Mesenchymal stem cells showed better adherence and a reduced proliferation on BMP-containing scaffolds. This was accompanied by an increase in gene expression of ALP, OC and COL-I. Furthermore the presence of BMP-2 resulted in an upregulation of FAK, while collagen had an impact on the gene expression of Smad5. Therefore these different strategies can be combined in order to enhance the osteoblast differentiation of hMSC on PLLA based nanofiber scaffold. By doing this, different signal transduction pathways seem to be up regulated.


Pharmacotherapy in alcoholism treatment: integrating and understanding the use of serotonin reuptake inhibitors.
Recently, a new area of alcohol-related pharmacotherapy has emerged, namely, the use of drugs which decrease drinking by either decreasing the reinforcing effects of alcohol or by decreasing other CNS-related factors associated with craving and/or motivation to drink. Reinforcement and motivation, as distinct components of drug consumption, might each be therapeutically altered. Evidence suggests that serotonergic systems are involved in aspects of motivation and perhaps also reinforcement, and thus may be important targets for alcohol-related pharmacotherapies. There is a substantial body of animal model literature to support this hypothesis, and recent clinical findings using serotonin reuptake inhibitors (SSRIs) are also supportive. Effective alcoholism treatment strategies with SSRIs should include consideration of the positive and negative impact on reinforcement and motivational factors, through both pharmacological and psychosocial means. In this way, pharmacotherapy with SSRIs will become useful not merely as an adjunctive treatment for alcohol-related disorders, but will become an integral part of the treatment process. Recent indications from clinical trials suggest that this integration may produce a synergistic effect on eventual patient outcome and quality of life.


Sources, spatial-distributions and fluxes of PAH-contaminated dusts in the Athabasca oil sands region.
Atmospheric deposition of polycyclic aromatic hydrocarbons (PAHs) has increased in northern Alberta, Canada, due to industrial development in the Athabasca oil sands region (AOSR). However, the sources, summertime deposition fluxes and associated spatial patterns are poorly characterized, and the magnitude of contamination has not been directly contrasted with comparable measurements around large Canadian cities. PAHs were measured in Sphagnum moss collected from 30 bogs in the AOSR and compared with reference moss collected from various remote, rural and near-urban sites in Alberta and Ontario. At all 39 locations, strong correlations between depositional fluxes of PAHs and accumulation rates of ash (n = 117, r = 0.877, p < 0.001) implied that the main source of PAHs to moss was atmospheric deposition of particles. Average PAH concentrations at near-field AOSR sites (mean [SD], 62.4 [24.3] ng/g) were significantly higher than at far-field AOSR sites (44.9 [20.8] ng/g; p = 0.038) or the 7 reference sites in Alberta (20.6 [3.5] ng/g; p < 0.001). In fact, average PAH concentrations across the entire AOSR (7,850 km2) were approximately twice as high as in London, Ontario, or near petroleum upgrading and major traffic corridors in Edmonton, Alberta. A chemical mass balance model estimated that both delayed petcoke (33 % of PAHs) and fine tailings (38 % of PAHs) were the major sources of PAHs in the AOSR. Over the 2015 summer growing season, we estimate that 101-110 kg of PAHs (on 14,300-17,300 tonnes of PAH-containing dusts) were deposited to the AOSR within a 50 km radius of surface mining. Given that the highest PAH deposition was to the northern quadrant of the AOSR, which includes the First Nations community of Fort MacKay, further dust control measures should be considered to protect human and environmental health in the region.


[Physical diagnosis--plantar reflex].
On stimulation of the plantar surface an extensor response of the toes (especially the big toe; Babinski sign) indicates a disorder of the corticospinal system: disinhibition of reflex activity causes the big toe to be recruited into the synergistic flexion reflex of the leg (toe extensors are flexors in a physiological sense). Proper assessment of the plantar reflex therefore involves not only rating toe movements, but also observing simultaneous contraction of flexor muscles in the thigh. Disregard of the association with the flexion synergy has given rise to some misunderstandings.


[Typhoid and paratyphoid fever in adults in the Internal Medicine Department at Libreville (Gabon)].
We carried out a retrospective study of 150 files of patients suffering from typhoid or paratyphoid fever, confirmed bacteriologically, between January 1992 and December 1996 at Libreville. Young adults were the most frequently affected. These infections were associated with unstable living conditions and lack of cleanliness. Neurological (17%), digestive (12%) and cardiovascular (3%) complications were the principal factors aggravating the disease. The following serotypes were identified: Salmonella typhi (47%), S. paratyphi B (25%), S. paratyphi C (20%) and S. paratyphi A (8%). Salmonellosis was associated with schistosomiasis (13%), nematodiasis (2.3%), sickle-cell anemia (7%) and HIV infection (8%). The mortality rate was 3.3%. Fluoroquinolones are the molecules of choice for treating typhoid and paratyphoid fevers.


Evaluation of antinociceptive activity of nanoliposome-encapsulated and free-form diclofenac in rats and mice.
Diclofenac is a nonsteroidal anti-inflammatory drug (NSAID) that exhibits anti-inflammatory, antinociceptive, and antipyretic activities. Liposomes have been shown to improve the therapeutic efficacy of encapsulated drugs. The present study was conducted to compare the antinociceptive properties between liposome-encapsulated and free-form diclofenac in vivo via different nociceptive assay models. Liposome-encapsulated diclofenac was prepared using the commercialized proliposome method. Antinociceptive effects of liposome-encapsulated and free-form diclofenac were evaluated using formalin test, acetic acid-induced abdominal writhing test, Randall-Selitto paw pressure test, and plantar test. The results of the writhing test showed a significant reduction of abdominal constriction in all treatment groups in a dose-dependent manner. The 20 mg/kg liposome-encapsulated diclofenac demonstrated the highest antinociceptive effect at 78.97% compared with 55.89% in the free-form group at equivalent dosage. Both liposome-encapsulated and free-form diclofenac produced significant results in the late phase of formalin assay at a dose of 20 mg/kg, with antinociception percentages of 78.84% and 60.71%, respectively. Significant results of antinociception were also observed in both hyperalgesia assays. For Randall-Sellito assay, the highest antinociception effect of 71.38% was achieved with 20 mg/kg liposome-encapsulated diclofenac, while the lowest antinociceptive effect of 17.32% was recorded with 0 mg/kg liposome formulation, whereas in the plantar test, the highest antinociceptive effect was achieved at 56.7% with 20 mg/kg liposome-encapsulated diclofenac, and the lowest effect was shown with 0 mg/kg liposome formulation of 8.89%. The present study suggests that liposome-encapsulated diclofenac exhibits higher antinociceptive efficacy in a dose-dependent manner in comparison with free-form diclofenac.